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[Cisplatin resistance in a murine leukemia cell line associated with defect of apoptosis]

E Segal-Bendirdjian1, A Jacquemin-Sablon

  • 1Unité de physicochimie et pharmacologie des macromolécules biologiques (URA147), Villejuif, France.

Bulletin Du Cancer
|May 1, 1996
PubMed

Insights

Cisplatin resistance in leukemia cells stems from altered apoptosis mechanisms, specifically a lack of nuclear endonuclease activity. However, a functional apoptosis pathway remains, involving cytoplasmic endonuclease, suggesting different activation routes in resistant cells.

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Pharmacology

Background:

  • Anticancer drugs like cisplatin can induce apoptosis, a programmed cell death process.
  • Cellular resistance to chemotherapy can arise from alterations in apoptosis pathways.
  • Understanding these mechanisms is crucial for developing more effective cancer treatments.

Purpose of the Study:

  • To investigate if altered apoptosis mechanisms contribute to cisplatin resistance in a murine leukemia cell line.
  • To compare the apoptotic response of a cisplatin-resistant cell line (L1210/DDP) with its wild-type counterpart (L1210/0).

Main Methods:

  • Induction of apoptosis was studied using cisplatin and 5-azacytidine in L1210/DDP and L1210/0 cells.
  • Assessed DNA fragmentation and morphological changes indicative of apoptosis.
  • Measured nuclear and cytoplasmic endonuclease activity.
  • Utilized staurosporine, a protein kinase C inhibitor, to probe apoptosis pathways.

Main Results:

  • The cisplatin-resistant L1210/DDP cells showed resistance to 5-azacytidine, a drug with a different mechanism of action.
  • L1210/DDP cells failed to exhibit typical apoptosis (DNA fragmentation, morphological changes) upon exposure to cisplatin or 5-azacytidine.
  • This failure correlated with a lack of nuclear endonuclease activity in resistant cells.
  • Staurosporine induced apoptosis in both cell lines, indicating a preserved functional apoptosis pathway.
  • Apoptosis induction by staurosporine in resistant cells involved cytoplasmic endonuclease activity, distinct from the wild-type cells.

Conclusions:

  • Cisplatin resistance in L1210/DDP cells is associated with impaired nuclear endonuclease activity, preventing typical apoptosis induction by certain drugs.
  • A functional apoptosis pathway exists in resistant cells, activated via cytoplasmic endonuclease, suggesting altered apoptotic signaling.
  • The nature and subcellular localization of endonuclease activity differ between cisplatin-sensitive and resistant leukemia cells, highlighting distinct apoptosis regulation mechanisms.

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